Genetic linkage of IgA deficiency to the major histocompatibility complex:Evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition

Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of te rminal lymphocyte differentiation, leading to a lack of IgA in serum and mu cosal secretions. Familial clustering, variable population prevalence in di fferent ethnic groups, and a predominant inheritance pattern suggest a stro ng genetic predisposition to IgAD. The genetic susceptibility to IgAD is sh ared with a less prevalent, but more profound, defect called "common variab le immunodeficiency" (CVID). Here we show an increased allele sharing at 6p 21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicati ng the presence of a predisposing locus, designated "IGAD1," in the proxima l part of the major histocompatibility complex (MHC). The recurrence risk o f IgAD was found to depend on the sex of parents transmitting the defect: a ffected mothers were more likely to produce offspring with IgAD than were a ffected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected un der random segregation. The differential parent-of-origin penetrance is pro posed to reflect a maternal effect mediated by the production of anti-IgA a ntibodies tentatively linked to IGAD1. This is supported by higher frequenc y of anti-IgA-positive females transmitting the disorder to children, in co mparison with female IgAD nontransmitters, and by linkage data in the forme r group. Such pathogenic mechanisms may be shared by other MHC-linked compl ex traits associated with the production of specific autoantibodies, parent al effects, and a particular MHC haplotype.